Abstract Influenza is a serious and potentially life-threatening viral disease characterized by periodic global outbreaks that claim hundreds of thousands of lives. During the 2017-2018 season, influenza caused nearly 80,000 deaths in the U.S., alone, leading to 23 million medical visits and 1 million hospitalizations. The burden of influenza on American healthcare is estimated at $11.2 billion annually, with $3.2 billion in direct medical costs. Vaccination programs can reduce the number of flu cases, but the existence of multiple strains and the continual emergence of new ones make it impossible to eliminate the disease or ensure that vaccine stockpiles will offer protection from the next pandemic. The symptoms of influenza ? a spectrum that runs from a runny nose and sore throat to acute respiratory distress and multi-organ dysfunction ? are ?side effects? of a functioning immune system. Patients that develop severe influenza suffer from an overactive and sustained immune response initiated by the release of cell signaling molecules in a process referred to as a cytokine storm. Viral load is of little use as a predictor of influenza outcomes and several studies have recorded poor patient responses to antiviral drugs. Further, a third of the antivirals approved for influenza are ineffective for certain virus strains, an influenza strain can develop resistance to any antiviral, and resistance is sometimes found at significant levels in outbreak strains. CytoAgents is developing a small molecule pharmaceutical to treat severe influenza. Our platform technology employs a well-studied compound, GP1681, that was found to be safe and well-tolerated in multiple clinical studies; but the compound had NOT been previously investigated as an influenza therapeutic. Notably, in animal model experiments using mice infected with influenza H5N1, our preliminary data demonstrated that GP1681 increased survival from 15% to 60%, while a combination treatment that also included an antiviral resulted in 100% survival. The initiation of Phase 1a clinical trials of our lead has been approved, however, the U.S. Food and Drug Administration has recommended some additional development activities and nonclinical evaluation studies. Thus, our specific aims in this Direct to Phase II project are: Aim 1: In vitro analyses of GP1681's effects on influenza virus replication, binding to human prostanoid receptors, and competition with EP4 agonists. Aim 2: Ex vivo analysis of release of 20 cytokines from peripheral blood mononuclear cells derived from multiple individuals and different racial backgrounds. Aim 3: In vivo assessment of GP1681 efficacy in mouse influenza challenge models, including dose response of GP1681, efficacy of delayed GP1681 treatment, effects of GP1681 against antiviral-resistant and multiple strains of influenza, and synergistic activity of GP1681 with existing antivirals. These studies will accompany initial clinical trials to evaluate the safety and efficacy of our lead compound and its eventual commercial deployment, with influenza as a first indication for a New Drug Application (NDA). Ultimately, treatment with GP1681 has the potential to benefit patients with any influenza-like-illness (ILI).